Genomic, transcriptomic and RNA editing analysis of human MM1 and VV2 sporadic Creutzfeldt-Jakob Disease
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ABSTRACT:
PROVIDER: PRJEB57720 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| 1.vcf.csi | Other | |||
| 1.vcf.gz | Vcf | |||
| 10.vcf.csi | Other | |||
| 10.vcf.gz | Vcf | |||
| 11.vcf.csi | Other |
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Project description:Creutzfeldt-Jakob disease (CJD) is characterized by a broad phenotypic spectrum regarding symptoms, progression, and molecular features. Current sporadic CJD (sCJD) classification recognizes six main clinical-pathological phenotypes. This work investigates the molecular basis of the phenotypic heterogeneity of prion diseases through a multi-omics analysis of the two most common sCJD subtypes: MM1 and VV2. We performed DNA target sequencing on 118 genes on a cohort of 48 CJD patients and full exome RNA sequencing on post-mortem frontal cortex tissue on a subset of this cohort. DNA target sequencing identified multiple potential genetic contributors to the disease onset and phenotype, both in terms of coding, damaging-predicted variants, and enriched groups of SNPs in the whole cohort and the two subtypes. The results highlight a different functional impairment, with VV2 associated with higher impairment of the pathways related to dopamine secretion, regulation of calcium release and GABA signaling, showing some similarities with Parkinson's disease both on a genomic and a transcriptomic level. MM1 showed a gene expression profile with several traits shared with different neurodegenerative, without an apparent distinctive characteristic or similarities with a specific disease. In addition, integrating genomic and transcriptomic data led to the discovery of several sites of ADAR-mediated RNA editing events, confirming and expanding previous findings in animal models. On the transcriptomic level, this work represents the first application of RNA sequencing on CJD human brain samples. Here, a good clusterization of the transcriptomic profiles of the two subtypes was achieved, together with the finding of several differently impaired pathways between the two subtypes. The results add to the understanding of the molecular features associated with sporadic CJD and its most common subtypes, revealing strain-specific genetic signatures and functional similarities between VV2 and Parkinson's disease and providing preliminary evidence of RNA editing modifications in human sCJD.
| S-EPMC9749175 | biostudies-literature
Project description:Sporadic Creutzfeldt-Jakob disease (sCJD) presents as a rapidly progressive dementia which is usually fatal within six months. No clinical blood tests are currently available for diagnosis or disease monitoring. Here, we profiled blood microRNA (miRNA) expression in sCJD. Small RNA-sequencing of 57 sCJD patients and 48 healthy controls revealed differential expression of hsa-let-7i-5p, hsa-miR-16-5p, hsa-miR-93-5p and hsa-miR-106b-3p. Downregulation of hsa-let-7i-5p, hsa-miR-16-5p and hsa-miR-93-5p replicated in an independent cohort using quantitative PCR, with concomitant upregulation of four of their mRNA targets. Absence of correlation in cross-sectional analysis with clinical phenotypes paralleled the lack of association between rate of decline in miRNA expression and rate of disease progression in a longitudinal cohort of 50 samples from 21 sCJD patients. Finally, the miRNA signature showed a high level of accuracy in discriminating sCJD from Alzheimer’s disease (AD). These findings highlight novel molecular alterations in the periphery in sCJD which can provide information about differential diagnosis and improve mechanistic understanding of human prion diseases.
2020-01-13 | GSE140069 | GEO
Project description: Not available
| S-EPMC6182307 | biostudies-literature
Project description:Background and purposeSporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly progressive neurodegenerative disease caused by an abnormal isoform of the human prion protein. Structural magnetic resonance imaging in patients with pathologically confirmed sCJD was compared with cognitively normal individuals to identify a cortical thickness signature of sCJD.MethodsThis retrospective cross-sectional study compared patients with autopsy-confirmed sCJD with dementia (n = 11) with age- and sex-matched cognitively normal individuals (n = 22). We identified regions of interest (ROIs) in which cortical thickness was most affected by sCJD. Within patients with sCJD, the relationship between ROI cortical thickness and clinical measures (disease duration, cerebrospinal fluid tau and diffusion-weighted imaging abnormalities) was evaluated.ResultsCompared with cognitively normal individuals, patients with sCJD had significantly reduced cortical thickness in multiple ROIs, including the fusiform gyrus, precentral gyrus, precuneus and superior temporal gyrus bilaterally; the caudal middle frontal gyrus, superior frontal gyrus, postcentral gyrus, inferior temporal gyrus and transverse temporal gyrus in the left hemisphere; and the superior parietal lobule in the right hemisphere. Only one patient with sCJD had co-pathology consistent with Alzheimer's disease. Reduced cortical thickness did not correlate with disease duration, presence of diffusion restriction or elevated cerebrospinal fluid tau.ConclusionCortical signature changes in sCJD may reflect brain changes not captured by standard clinical measures. This information may be used with clinical measures to inform the progression of sCJD and patterns of prion protein spread throughout the brain. These results may have implications for prediction of symptomatic progression and plausibly for development of therapeutic strategies.
| S-EPMC6615963 | biostudies-literature
Project description:Gene expression in the brain of sporadic Creutzfeldt-Jakob disease patients (CJD), and normal controls (CT)
| PRJNA672339 | ENA
Project description:Neuroinflammation is an essential part of neurodegeneration. Yet, current understanding of neuroinflamma-tion associated molecular events in distinct brain regions of prion disease patients is insufficient to lay the ground for effective treatment strategies targeting this complex neuropathological process. To address this problem, we analyzed expression of 800 neuroinflammation associated genes to create a profile of biological processes taking place in frontal cortex and cerebellum of patients, who suffered from sporadic Creutzfeldt-Jakob disease. The analysis was performed using NanoString nCounter technology, human neuroinflamma-tion panel+. The observed gene expression patterns indicate regionally, and sub-regionally common and dis-tinct molecular pathways associated with sporadic Creutzfeldt-Jakob disease pathogenesis. Moreover, the data show that the neuroinflammatory response in samples from the same brain region is variable. Based on the gene expression profiles from FC and CB, regional, neuroinflammatory patterns were observed.
2021-01-08 | GSE160208 | GEO
Project description:ImportanceSporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly lethal disease. Rapid, accurate diagnosis is imperative for epidemiological surveillance and public health activities to exclude treatable differentials and facilitate supportive care. In 2017, the International CJD Surveillance Network diagnostic criteria were revised to incorporate cortical ribboning on magnetic resonance imaging and the real-time quaking-induced conversion (RT-QuIC) assay, developments that require multicenter evaluation.ObjectiveTo evaluate the accuracy of revised diagnostic criteria through the retrospective diagnosis of autopsy-confirmed cases (referred to as in-life diagnosis).Design, setting, and participantsThis diagnostic study used a 3-year clinicopathological series using all cases of autopsy-confirmed sCJD and a noncase group with alternative neuropathological diagnoses from national surveillance centers in the United Kingdom, France, Germany, and Italy. Data were collected from January 2017 to December 2019 and analyzed from January 2020 to November 2021.Main outcomes and measuresSensitivity and specificity of revised diagnostic criteria and diagnostic investigations. Secondary analyses assessing sCJD subgroups by genotype, pathological classification, disease duration, and age.ResultsA total of 501 sCJD cases and 146 noncases were included. Noncase diagnoses included neurodegenerative diseases, autoimmune encephalitis, and cerebral insults such as anoxia. Participants in the sCJD cases cohort were younger (mean [SD] age, 68.8 [9.8] years vs 72.8 [10.9] years; P < .001) and had longer median (IQR) disease duration (118 [74.8-222.3] days vs 85 [51.5-205.5] days; P = .002); sex ratios were equivalent (253 [50.5%] male cases vs 74 [50.7%] male noncases). Sensitivity of revised criteria in in-life diagnosis (450 of 488 [92.2%] diagnoses; 95% CI, 89.5%-94.4%) was increased compared with prior criteria (378 of 488 [77.5%] diagnoses; 95% CI, 73.5%-81.1%; P < .001), while specificity (101 of 125 [80.8%] diagnoses; 95% CI, 72.8%-87.3%) was unchanged (102 of 125 [81.6%] diagnoses; 95% CI, 73.7%-88.0%; P > .99). Among 223 cases and 52 noncases with the full panel of investigations performed, sensitivity of revised criteria (97.8%; 95% CI, 94.9%-99.3%) was increased compared with prior criteria (76.2%; 95% CI, 70.1%-81.7%; P < .001) while specificity was unchanged (67.3%; 95% CI, 52.9%-79.7% vs 69.2%; 95% CI, 54.9%-81.3%; P > .99). In 455 cases and 111 noncases, cortical ribboning was 67.9% sensitive (95% CI, 63.4%-72.2%) and 86.5% specific (95% CI, 78.7%-92.2%). In 274 cases and 77 noncases, RT-QuIC was 91.6% sensitive (95% CI, 87.7%-94.6%) and 100% specific (95% CI, 96.2%-100%). Investigation sensitivity varied with genetic and pathological features, disease duration, and age.Conclusions and relevanceThis diagnostic study demonstrated significantly improved sensitivity of revised sCJD diagnostic criteria with unaltered specificity. The revision has enhanced diagnostic accuracy for clinical care and surveillance.
| S-EPMC8804913 | biostudies-literature
Project description:Prion diseases are fatal and transmissible neurodegenerative disorders caused by the misfolding and aggregation of prion protein. Although recent studies have implicated epigenetic variation in common neurodegenerative disorders, no study has yet explored their role in human prion diseases. Here we profiled genome-wide blood DNA methylation in the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD). Our case-control study (n=219), when accounting for differences in cell type composition between individuals, identified 38 probes at genome-wide significance (p < 1.24x10-7). Nine of these sites were taken forward in a replication study, performed in an independent case-control (n=186) cohort using pyrosequencing. Sites in or close to FKBP5, AIM2 (2 probes), UHRF1, KCNAB2, PRNP, ANK1 successfully replicated. The blood-based DNA methylation signal was tissue- and disease-specific, in that the replicated probe signals were unchanged in case-control studies using sCJD frontal-cortex (n=84), blood samples from patients with Alzheimer’s disease, and from inherited and acquired prion diseases. Machine learning algorithms using blood DNA methylation array profiles accurately distinguished sCJD patients and controls. Finally, we identified sites whose methylation levels associated with prolonged survival in sCJD patients. Altogether, this study has identified a peripheral DNA methylation signature of sCJD with a variety of potential biomarker applications.
2020-10-19 | GSE156994 | GEO
Project description:The familial or genetic Creutzfeldt-Jakob disease (fCJD or gCJD) is the inherent form of human prion diseases, which accounts for approximately 10-15% of human prion diseases that are caused by mutations of the prion protein gene (PRNP). In this study, the global expression patterns of the parietal cortex from a patient with G114V gCJD were comparatively analyzed with the normal controls by using a commercial human genome expression chip. Totally 8774 genes showed differential expression, among them 2769 genes were upregulated and 6005 ones were downregulated. The reliability of the results was confirmed by the real-time RT-PCR assays for several specific genes. The most differentially expressed genes involved in the functions of regulation of transcription, ion transport, transcription, cell adhesion, signal transduction. The gene associated with gliosis was upregulated and the genes marked for neurons were downregulated, while the transcription of PRNP gene maintained unchanged. 169 different pathways showed significantly changed in the brain of G114V gCJD. The most significantly regulated pathways included that of Alzheimer’s and Parkinson’s disease, oxidative phosphorylation, regulation of actin cytoskeleton, MAPK signaling pathway and proteasome, which were described in prion diseases previously. In addition, some rarely addressed pathways in prion diseases, such as axon guidance, gap junction and purine metabolism, were also significantly changed in G114V gCJD. The transcriptional situations of the most genes in the top ten changed pathways were down-regulated. The extensive reductions of gene expressions in G114V gCJD showed the comparable profiles with sporadic CJD. The data here raised the useful clues for understanding the pathogenesis of the disease and selecting the potential biomarkers for diagnostic and therapeutic tools. Brain tissues of parietal cortex from a definitely diagnosed G114V gCJD were enrolled into this study. The patient was a 47-year-old Han-Chinese woman at the onset. Neuropathological assays of ten different brain regions revealed typical sCJD-like abnormality and PrPSc deposits. Meanwhile, a commercial normal human parietal cortex total RNA (Clontech) pooled from four male/female aged 35-89 was utilized as control.
2013-07-01 | E-GEOD-30643 | biostudies-arrayexpress
Project description:We aimed to identify targets for neuropalliative care interventions in sporadic Creutzfeldt-Jakob disease by examining characteristics of patients and sources of distress and support among former caregivers. We identified caregivers of decedents with sporadic Creutzfeldt-Jakob disease from the University of California San Francisco Rapidly Progressive Dementia research database. We purposively recruited 12 caregivers for in-depth interviews and extracted associated patient data. We analysed interviews using the constant comparison method and chart data using descriptive statistics. Patients had a median age of 70 (range: 60-86) years and disease duration of 14.5 months (range 4-41 months). Caregivers were interviewed a median of 22 (range 11-39) months after patient death and had a median age of 59 (range 45-73) years. Three major sources of distress included (1) the unique nature of sporadic Creutzfeldt-Jakob disease; (2) clinical care issues such as difficult diagnostic process, lack of expertise in sporadic Creutzfeldt-Jakob disease, gaps in clinical systems, and difficulties with end-of-life care; and (3) caregiving issues, including escalating responsibilities, intensifying stress, declining caregiver well-being, and care needs surpassing resources. Two sources of support were (1) clinical care, including guidance from providers about what to expect and supportive relationships; and (2) caregiving supports, including connection to persons with experience managing Creutzfeldt-Jakob disease, instrumental support, and social/emotional support. The challenges and supports described by caregivers align with neuropalliative approaches and can be used to develop interventions to address needs of persons with sporadic Creutzfeldt-Jakob disease and their caregivers.
| S-EPMC8896185 | biostudies-literature